Facial erythema of rosacea: brimonidine tartrate gel

Drug action

Brimonidine tartrate is a highly selective alpha‑2 adrenergic receptor agonist, with potent vasoconstrictive and vasostabilising activity. Erythema of rosacea is associated with permanent vasodilatation of small vessels. Facial application of brimonidine tartrate reduces erythema through direct cutaneous vasoconstriction (Brimonidine tartrate gel [Mirvaso] summary of product characteristics).

Licensed therapeutic indication

Brimonidine tartrate gel (Mirvaso) is indicated for the symptomatic treatment of facial erythema of rosacea in adults (Brimonidine tartrate gel [Mirvaso] summary of product characteristics).

Course and cost

Brimonidine tartrate gel (Mirvaso) is an aqueous gel that is applied to the face once every 24 hours, at any time that is suitable for the person, for as long as facial erythema is present. The maximum daily recommended dose is 1 g of gel, divided into 5 pea‑sized amounts. One gram of gel contains 3.3 mg of brimonidine, equivalent to 5 mg of brimonidine tartrate (Brimonidine tartrate gel [Mirvaso] summary of product characteristics). In a long‑term study (Moore et al. 2014) the average daily amount used was 0.532 g.

A small pea‑sized amount of gel is applied to each of the 5 areas of the face: forehead, chin, nose, and each cheek. The gel should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes, eyelids, lips, mouth and membrane of the inner nose.

Brimonidine tartrate gel should be applied only to the face. Hands should be washed immediately after applying the gel. Brimonidine tartrate gel can be used in conjunction with other topical medicinal products for treating inflammatory lesions of rosacea and with cosmetics. These products should not be applied immediately before the daily application of brimonidine tartrate gel; they may be used only after the applied gel has dried (Brimonidine tartrate gel [Mirvaso] summary of product characteristics).

The cost of brimonidine tartrate gel (Mirvaso) is £33.69 for a 30 g tube (excluding VAT; cost taken from MIMS, May 2014).

Clinical effectiveness

In both RCTs, 0.5% brimonidine tartrate gel (5 mg/g) was statistically significantly more effective than vehicle gel in reducing erythema. At day 29, the primary end point of 'success rate', defined as a 2‑grade improvement on both the clinician's (CEA) and patient's (PSA) assessment of erythema over 12 hours, was statistically significantly higher in the active compared with the vehicle gel groups in both studies based on the ITT population (both p<0.001; see tables 1 and 2 for details). Three hours after application the 'success rate' was 31.5% with brimonidine gel and 10.9% with vehicle gel in trial A, and 25.4% with brimonidine gel and 9.2% with vehicle gel in trial B. In both trials, the 'success rate' was also statistically significantly higher with active compared with vehicle gel on day 1 and day 15 (all p<0.001); and per‑protocol analyses and sensitivity analyses also gave similarly statistically significant differences (all p<0.05; Fowler et al. 2013).

The secondary end point of onset of efficacy (the '30‑minute effect'), defined as a 1‑grade improvement from baseline on both the CEA and PSA at 30 minutes on day 1, was also statistically significantly improved with 0.5% brimonidine tartrate gel compared with vehicle gel. The '30‑minute effect' was seen in 27.9% of the brimonidine gel group and 6.9% of the vehicle gel group in trial A, and 28.4% of the brimonidine gel group and 4.8% of the vehicle gel group in trial B (both p<0.001; Fowler et al. 2013).

Efficacy was also assessed using the less stringent measure of a 1‑grade improvement on both the clinician's (CEA) and patient's (PSA) assessment of erythema over 12 hours. Statistically significantly more participants in the brimonidine gel groups than in the vehicle gel groups had this response at day 1, 15 and 29 (all p<0.001; see table 1 and 2 for day 29 results). At day 29, 3 hours after application the 'responder rate' was 70.9% with brimonidine gel and 32.8% with vehicle gel in trial A, and 71.1% with brimonidine gel and 40.1% with vehicle gel in trial B (Fowler et al. 2013).

Maximal drug effects were typically observed 3 hours after application and continued for about 6 hours after application. The European public assessment report for Mirvaso states that there is some tapering off of the effect on rosacea by 12 hours after application, but at hour 12 there is still an approximate 1‑grade improvement on CEA or PSA relative to hour 0 with brimonidine tartrate gel.

Other end points included facial inflammatory lesions and telangiectasias. These symptoms of rosacea are not considered specific indications for brimonidine tartrate gel, but they were assessed to evaluate whether any worsening would occur. In both trials, baseline lesion scores were similar between the brimonidine gel and vehicle gel groups and no significant worsening was observed at hour 12 on day 29 or during the follow‑up period (weeks 6 and 8). The same was true for telangiectasias. In both trials, the Telangiectasia Grading Assessment (TGA) was similar between the groups at baseline, and there was no significant worsening in mean TGA scores at hour 12 on day 29 or during the follow‑up period (weeks 6 and 8) (European public assessment report for Mirvaso).

Because rebound effects and tachyphylaxis can occur after withdrawal of alpha‑2 adrenergic receptor agonists, both trials investigated the potential of brimonidine tartrate gel to show reduced efficacy over time or to cause more severe erythema after stopping treatment. There was no evidence of tachyphylaxis or loss of efficacy during the 4‑week treatment period in either trial (Fowler et al. 2013, European public assessment report for Mirvaso).

After treatment was stopped, no rebound erythema was seen compared with baseline during the 4‑week follow‑up period for either treatment group in both trials. Some individuals showed worsening in CEA and PSA scores relative to baseline during the follow‑up period; and more people in the brimonidine tartrate gel groups compared with the vehicle groups tended to experience worsening during the follow‑up period. The numbers were small, with less than 5% of people showing 1‑grade increases in CEA or PSA (European public assessment report for Mirvaso). However, case reports of possible rebound erythema have since been published (Routt and Levitt 2014) (see safety and tolerability section).

As well as rating their erythema with PSA, participants in the study rated their appearance with the Patient Assessment of Appearance (PAA) scale, assessed the overall impact of treatment with the Overall Treatment Effect (OTE) scale, and assessed the potential of brimonidine to over‑whiten the skin using the Patient Assessment of Whitening (PAW) scale.

Higher percentages of people in the brimonidine gel group were 'bothered by too much whitening' compared with the vehicle gel groups. However, the number of reports of unwanted over‑whitening decreased over the course of the trials, and there were no discontinuations because of over‑whitening (European public assessment report for Mirvaso).

The patient self‑assessment using the PAA scale showed that more people were satisfied with their appearance in the brimonidine gel groups compared with the vehicle gel groups. At day 29, more people were 'satisfied' or 'very satisfied' in the brimonidine gel groups ('very satisfied': 7.9%, 'satisfied': 35.4% in trial A; 'very satisfied': 9.2%, 'satisfied': 26.8% in trial B) than in the vehicle gel groups ('very satisfied': 0.8%, 'satisfied': 19.5% in trial A; 'very satisfied': 2.1%, 'satisfied': 16.9% in trial B); no statistical analyses were reported. The overall results from the assessment using the OTE scale also favoured brimonidine, with statistically significantly more people in the brimonidine gel groups reporting improvement in the management of their facial erythema compared with those in vehicle gel groups (p<0.001) (European public assessment report for Mirvaso).

However, PAA and OTE results also showed that a substantial number of people were not satisfied with their appearance or experienced worsening of the condition at the end of treatment. Based on PAA at day 29, 27.6% of people in the brimonidine gel group compared with 43.7% of people in the vehicle gel group were 'dissatisfied' or 'very dissatisfied' in trial A and 24.6% of people in the brimonidine gel group compared with 42.2% in the vehicle gel group were 'dissatisfied' or 'very dissatisfied' in trial B (no statistical analysis reported). For OTE, on day 29, twice as many participants in the active treatment group (10.1% in trial A and 10.1% in trial B) compared with the vehicle group (5.3% in trial A and 3.4% in trial B) considered that their condition had worsened as a result of the treatment (no statistical analysis reported). However, as the European public assessment report states, it is plausible that some people will relate the wearing off of the effect at the end of the day to a worsening, and that this is more pronounced in the active than the vehicle group. The overall OTE results showed that the majority of participants in the study experienced an improvement with brimonidine tartrate gel. The trials also included quality of life assessments, but no notable differences were seen between brimonidine tartrate and vehicle gel (European public assessment report for Mirvaso).

An open‑label, non‑comparative study carried out in the USA included 449 people with a clinical diagnosis of rosacea and moderate or severe erythema according to both the CEA and PSA (Moore et al. 2014). Participants applied a thin film of 0.5% brimonidine tartrate gel over the entire face once daily in the morning for up to 12 months. In contrast to the RCTs, inclusion of people with 3 or more inflammatory lesions and with concomitant standard treatments for inflammatory lesions of rosacea was allowed, which resulted in a study population that probably better reflects the true rosacea population (European public assessment report for Mirvaso).

As in the RCTs, most people were female (75%), Caucasian (98%), and with moderate erythema (88% based on CEA and 84% based on PSA). The mean age of the participants was 51 years and 29% were receiving concomitant treatments for inflammatory lesions of rosacea, such as metronidazole, azelaic acid, tetracycline, minocycline or doxycycline. Of the 449 people enrolled, 335 (74.6%) completed at least 6 months of treatment and 279 (62.1%) completed the study (up to the 12‑month visit) (Moore et al. 2014).

On day 1, after the first application of brimonidine tartrate gel, the mean CEA score decreased from 3.1 at hour 0 to 1.7 at hour 3. This improvement was maintained at each visit until month 12, when the mean CEA score reduced from 2.3 at hour 0 to 1.3 at hour 3. Similar results were seen with PSA, which decreased from 3.1 at hour 0 to 2.1 at hour 3 on day 1, and from 2.2 at hour 0 to 1.5 at hour 3 on the study visit at month 12 (no statistical analyses were reported). No tachyphylaxis or loss of efficacy was seen (Moore et al. 2014).

Safety and tolerability

In both RCTs, 0.5% brimonidine tartrate gel was generally well tolerated. Adverse events occurred in 29.5% of people in the brimonidine gel group and 25.2% of people in the vehicle gel group in trial A, and in 33.8% of the brimonidine gel group and 24.1% of the vehicle gel group in trial B (no statistical analysis reported). Treatment‑related adverse events were less frequent, occurring in 11.6% and 9.5% of the brimonidine gel groups in trial A and B respectively, and in 5.3% and 9.7% of the vehicle gel groups (no statistical analyses reported). In trial A, 2 people (1.6%) discontinued because of an adverse event in the active group compared with 1 person (0.8%) in the vehicle group; in trial B, 1 person (0.7%) discontinued because of an adverse event in each group (Fowler et al. 2013).

The most frequent treatment‑related adverse events with brimonidine in the 2 RCTs were worsening of erythema or flushing (7 people in each trial), pruritus (4 people in trial A and 1 person in trial B), skin irritation (3 people in trial A) and worsening of rosacea (1 person in trial A and 2 people in trial B). No serious treatment‑related adverse events occurred in either RCT, and no changes in blood pressure or heart rate were seen (Fowler et al. 2013).

In the open‑label, non‑comparative study (n=449), the incidence of adverse events was highest during the first quarter of the study (90 days) and declined after that. Overall, adverse events were reported by 61.2% of people, and treatment‑related adverse events by 31.0% of people. The most frequent treatment‑related adverse events were flushing (9.1%), worsening of erythema (6.5%), worsening of rosacea (3.6%), skin burning sensation (3.3%), skin irritation (3.1%), contact dermatitis (2.2%) and pruritus (2.0%). There was 1 death from lung cancer and 16 serious adverse events during the study, all of which were deemed unrelated to the study drug. There were no abnormal trends in blood pressure, heart rate or intraocular pressure during the study (Moore et al. 2014).

The brimonidine tartrate gel summary of product characteristics states that the most commonly reported adverse reactions are erythema, pruritus, flushing and skin burning sensation, all occurring in between 1.2% and 3.3% of people in clinical studies. They are typically mild to moderate in severity, and usually do not require discontinuation of treatment.

Brimonidine tartrate gel is contraindicated in people receiving monoamine oxidase inhibitors (for example selegiline or moclobemide) or tricyclic (such as imipramine) or tetracyclic (such as maprotiline, mianserin or mirtazapine) antidepressants. It is also contraindicated in children aged less than 2 years and should not be used in children or young people aged 2 to 18 years. Safety concerns related to the systemic absorption of brimonidine have been identified for the age group 2 to 12 years. Brimonidine tartrate gel should not be applied on irritated skin or open wounds, or close to the eyes. In the case of severe irritation or contact allergy, treatment should be discontinued. Any increase in the daily amount applied and/or frequency of application should be avoided, because the safety of higher daily doses or repeated daily application has not been assessed (Brimonidine tartrate gel [Mirvaso] summary of product characteristics).

The summary of product characteristics states that no clinically meaningful trends with respect to tachyphylaxis or rebound effects (worsening of erythema after stopping treatment) were seen with the use of brimonidine tartrate gel for 29 days. However, a report of severe erythema and burning sensation in 3 people using brimonidine tartrate gel has recently been published (Routt et al. 2014). The authors state that these could be rebound vasodilation reactions to brimonidine, similar to rebound nasal congestion seen with overuse of alpha‑adrenergic agonist nasal sprays. They suggest that counselling people about the potential for worsening erythema, use of a test area, and limiting use to special occasions may be warranted.

Evidence strengths and limitations

The 2 randomised, vehicle‑controlled phase III trials (Fowler et al. 2013) were well‑designed and well‑conducted, with no major differences between the active treatment and the vehicle groups in baseline characteristics. In both trials, patients and clinicians were blinded to which treatment they were given, but some degree of unblinding was possible because of the clinical effects of brimonidine on the skin.

Both trials were short‑term (4‑week treatment phase and 4‑week follow‑up phase) and compared brimonidine tartrate gel with vehicle gel, not an active comparator; although, because there are no approved medicinal products in Europe that directly target facial erythema of rosacea, this is probably reasonable. Long‑term efficacy and safety data are limited to that available from the open‑label, non‑comparative study, which followed people for up to 12 months (Moore et al. 2014).

Brimonidine tartrate gel is licensed for the symptomatic treatment of facial erythema of rosacea in adults (Brimonidine tartrate gel [Mirvaso] summary of product characteristics). However, the 2 RCTs and the open‑label study were conducted in people with moderate to severe erythema (marked or fiery redness) according to both the CEA and PSA. There is no evidence for the use of brimonidine tartrate gel in people with less severe erythema, which could represent a substantial proportion of the primary care population.

The European public assessment report for Mirvaso (EPAR) states that there is no European guideline available for products indicated for the treatment of rosacea, and efficacy end points are not clearly established. Therefore, the manufacturer developed the clinician assessment (CEA) and patient assessment (PSA) scales used in these RCTs. Both of these scales are based on subjective judgements and not objective measures. However, considering the type of condition and the intended use of the product (symptomatic reduction of erythema rather than curative treatment), the EPAR states that these scales are sufficiently described and validated for their intended purpose. The primary efficacy end point was a 2‑grade improvement on both the CEA and PSA over 12 hours. The authors of the phase II studies (Fowler et al. 2012) stated that this was a stringent criterion for success required for regulatory approval. They suggest a 1‑grade improvement on both CEA and PSA represents an effect that is noticeable by both investigators and patients, and is therefore clinically relevant. However, specialists have suggested that without further validation, defining what a clinically important change is on these scales is difficult.

The European public assessment report for Mirvaso states that the efficacy and safety of brimonidine tartrate gel in people whose condition is being treated with other topical products for rosacea, such as metronidazole or azelaic acid gel, has not been systematically investigated. However, in the open‑label, long‑term study, other rosacea treatments were allowed and, although not large numbers, 70 people used metronidazole gel and 27 used azelaic acid gel.

Alternative treatments

There are no other approved medicinal products in Europe that directly target facial erythema of rosacea, and management generally consists of lifestyle advice. Off‑label propranolol or clonidine may be used to treat flushing (Primary Care Dermatology Society guidance on rosacea), but this use is not supported by evidence from RCTs. For persistent erythema or telangiectasia, laser therapy can be effective although improvement is not permanent, and this may not be available on the NHS. Camouflage cream is also used.

Mild or moderate papulopustular rosacea is usually treated with topical metronidazole or azelaic acid. The activity of these drugs on underlying erythema and flushing is based on reduction of inflammatory redness and long term action on small vessels, but they provide no immediate and evident improvement of baseline erythema that can be evident in the short term (European public assessment report for Mirvaso).

For moderate or severe papulopustular rosacea, oral tetracycline, erythromycin, doxycycline or lymecycline can be prescribed, although not all of these drugs are licensed for treating rosacea (Clinical Knowledge Summaries: rosacea) and RCT data to support their use are limited (van Zuuren et al. 2011).

Costs of topical treatments for rosacea

Likely place in therapy

The 2 short‑term RCTs showed that in people with moderate to severe erythema (marked or fiery redness), brimonidine tartrate gel had a statistically significant effect on erythema compared with vehicle gel. It had a rapid onset of effect (within 30 minutes in 28% of people) that was partially maintained over a 12‑hour period, although efficacy peaked at about 3 hours. However, response rates for a 2‑grade reduction in the severity of erythema as assessed by both patients and clinicians were just 25% to 30% with brimonidine gel (compared with about 10% for vehicle gel) at day 29.

The majority of people experienced an overall improvement with brimonidine tartrate gel, and more people were satisfied with their appearance in the brimonidine gel groups compared with the vehicle gel groups. However, about 26% of people using brimonidine gel (compared with about 40% in the vehicle gel groups) were not satisfied with their appearance after 4 weeks of treatment.

Brimonidine tartrate gel is not indicated for papulopustular rosacea and there is only limited data on its use in people treated with other topical products for this, such as metronidazole or azelaic acid gel. The summary of product characteristics states that brimonidine tartrate gel can be used in conjunction with these other topical treatments: they should not be applied immediately before the daily application of brimonidine gel, but after the brimonidine gel has dried.

The European public assessment report for Mirvaso states that limited long‑term efficacy data are available, but a comparison of results across studies has shown a similar level of activity after 4 weeks and after 1 year of use, suggesting that efficacy is maintained over time.

Brimonidine tartrate gel is generally well‑tolerated with mainly local adverse events such as erythema, pruritus, flushing and skin burning sensation. The European public assessment report for Mirvaso states that these are common adverse events for other topically applied medicinal products, for instance metronidazole gel, and do not raise cause for concern. However, a case report of possible rebound erythema in 3 people has recently been published (Routt et al. 2014).

The cost of brimonidine tartrate gel (Mirvaso) is £33.69 for a 30 g tube (excluding VAT; cost taken from MIMS, May 2014).

Brimonidine tartrate gel is the first medicinal product to be approved for the symptomatic treatment of facial erythema of rosacea. It may be an option for adults with a clinical diagnosis of rosacea and moderate to severe erythema (marked or fiery redness) because this was the population assessed in the clinical trials. However, specialists have advised that it is important to ensure that lifestyle recommendations, such as using high‑factor sunscreen and avoiding trigger factors, have been optimised before brimonidine is considered, and that these are continued throughout treatment with brimonidine.

Rosacea is a chronic condition, and although brimonidine tartrate gel has a transient effect on erythema, it does not alter the course of the disease or have any effect on other features of rosacea, such as telangiectasia or inflammatory papules. It can be used up to once per day, but does not need to be used daily, and specialists have suggested that some people may only use brimonidine tartrate gel on days when they feel their appearance is particularly important. Before continuing longer‑term treatment with brimonidine, consideration will need to be given to how treatment efficacy can be assessed given the subjective nature of efficacy outcomes and the low response rates seen in clinical trials. Not everyone will respond to treatment and some assessment of the continuing need for treatment would seem appropriate.

Local decision makers will need to take into account the evidence for the efficacy and safety of brimonidine tartrate gel, factors relating to individual people with rosacea and cost.

Estimated usage

It is not possible to provide estimated usage based on the available data.

Expert advisers

Dr Julian Peace, GP, Valley Medical Centre, Stocksbridge; GPSI Dermatology Barnsley NHSFT

Dr Shernaz Walton, Consultant Dermatologist, Hull and East Yorkshire Hospitals NHS Trust

Professor Hywel Williams, Professor of Dermato‑Epidemiology and Director of the Centre of Evidence‑Based Dermatology, University of Nottingham

Dr Esther van Zuuren; Department of Dermatology, Leiden University Medical Centre, Netherlands

Declarations of interest

No relevant interests declared.

Changes after publication

October 2015: Minor maintenance.

Copyright

© National Institute for Health and Care Excellence, 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.

ISBN 978‑1‑4731‑0633‑8